Innovative Pyrazole–Thiazole–Oxadiazole Hybrid Compounds for Targeted EGFR/VEGFR2 Inhibition in Cancer Treatment

A new series of pyrazole–thiazole–oxadiazole hybrid compounds targeting the EGFR and VEGFR2 enzymes was designed and synthesized using innovative approaches. The compounds were characterized through spectral methods, and their cytotoxic activities were evaluated against the A549 lung and HT-29 colon cancer cell line using the MTT assay. Among them, compounds 17i and 17m exhibited notable cytotoxicity, with 17i demonstrating approximately threefold greater activity compared to the reference drug sorafenib for A549 cells. Flow cytometry analysis revealed that 17i induced extensive necrotic cell death, while 17m triggered a more targeted and controlled apoptotic mechanism. In vitro enzyme inhibition assays demonstrated that 17i inhibited EGFR and VEGFR2 with IC₅₀ values of 0.158 and 0.128 µM, respectively. In contrast, 17m exhibited more potent inhibition of EGFR (IC₅₀ = 0.012 µM) and moderate activity against VEGFR2 (IC₅₀ = 0.309 µM). Molecular docking and molecular dynamics simulations further supported the structural stability of the complexes formed by these compounds with their target enzymes, highlighting their potential as effective enzyme inhibitors. Collectively, these findings suggest that pyrazole–thiazole–oxadiazole hybrids represent promising candidates for targeted cancer therapy at the cellular level.